The human tau protein has been implicated in the pathogenesis of several human neurodegenerative diseases including Alzheimer's disease (AD) and frontal temporal lobe dementia (Hardy et al. 1998, Spillantini and Godert 1998). The pathology of AD is defined as the presence of amyloid-containing plaques and neurofibrillary tangles (NFTs) composed of tau arranged into paired helical filaments (PHFs). Mutations in the tau gene lead to a range of tauopathies (termed Fronto-Temporal Dementia and Parkinsonism linked to chromosome 17 (FTDP-17) where tau takes the form of PHF (Spillantini et al. 1996, Poorkaj et al. 1998, Hutton et al. 1998) or twisted ribbons (Spillantini et al. 1997, 1998, Hutton et al. 1998, Reed et al. 1998). Although the mechanisms underlying the development of tauopathy in these diseases are unknown, hyperphosphorylation of tau has been linked to AD (Iqbal and Iqbal 1996), and disruption of microtubule binding and assembly has been linked to FTDP-17 missense mutations (Hasegawa et al. 1998, Hong et al. 1998).
Human tau is alternatively spliced to generate six isoforms that differ in the presence of absence of exons 2, 3 or 10 (Godert et al. 1989, Andreadis et al. 1992). Splicing out of exon 10 generates a tau protein with 3 microtubule binding domain repeats (3R), whereas its inclusion generates tau with 4 repeats (4R). The normal human brain maintains an approximately equal ratio of 4R to 3R tau but this ratio is shifted in favor of more 4R tau in FTDP-17 patients with splice site mutations (Godert and Jakes 1990, Spillantini et al. 1998, Hong et al. 1998, Godert et al. 1999, Grover et al. 1999). Biochemical evidence suggests that microtubule binding and assembly is disrupted by some missense mutations in tau (Hasegawa et al. 1998, Hong et al. 1998, Dayanandan et al. 1999), however, the mechanism by which excess 4R tau causes neuronal degeneration is less clear. Given that excess 4R tau is detrimental to humans, it is surprising that the normal adult mouse makes 4R tau exclusively (Gotz et al. 1995, Kampers et al. 1999), although it is possible that in FTDP-17, a shift in the normal ratio of tau isoforms is pathogenic rather than their absolute levels.
Thus, what is needed is a non-human animal model which expresses human tau, e.g., to examine the normal biology of tau and to provide a model for tauopathies where the ratio of tau isoforms are shifted.